PROJECT 4: DETERMINING THE ABILITY OF RAPAMYCIN TO IMPROVE LIFESPAN AND HEALTHSPAN IN COMPANION DOGS ABSTRACT A primary goal of geroscience is to improve health, longevity, and quality of life for people through basic and translational research into the biology of aging. While there has been significant progress in understanding the basic mechanisms of aging and developing interventions to delay aging in laboratory models, to date there has been limited application of these findings in a clinical setting. This project aims to take a first step toward such translational application by testing whether treatment with rapamycin can increase lifespan and improve healthspan in companion (pet) dogs, similar to what has been observed in laboratory mice. This will be accomplished through a double-blind, placebo-controlled veterinary clinical trial involving 300 healthy, middle- aged (at least 6 years old), larger (at least 18 kg) companion dogs. Dogs will be randomized into either placebo, transient (6 months) or continuous (3 years) treatment groups and the effect of rapamycin on survival and overall health during aging will be assessed. Measures of health will include assessments of mobility, frailty, and disease incidence (in collaboration with Project 1). In addition, given the reported beneficial effects of rapamycin treatment on cardiac and cognitive function in older mice, there will be a special emphasis on assessing the effects of rapamycin on cognitive function (with Core C) and cardiac function in dogs. In collaboration with Project 3, the effects of rapamycin treatment on systemic metabolism and the intestinal microbiome in companion dogs will be assessed through serum metabolomics and analysis of bacterial composition of fecal samples, respectively. Overall, this study will advance our understanding of the interaction between mTOR signaling and basic aging processes in dogs living in the human environment and could potentially extend the healthspan and lifespan of dogs, thus improving the quality of life for both dogs and their owners.